Project Summary In 2014 there were an estimated 9.6 million cases of tuberculosis (TB) disease with 1.5 million deaths due to TB, more deaths than from any other single infectious agent. Bacille Calmette Guerin (BCG), a live attenuated Mycobacterium bovis (M.bovis), is the only licensed vaccine against TB. Although it is efficacious against severe forms of childhood TB when administered to newborn infants, it provides little or no protection against pulmonary TB in adolescents/adults, who are the major source of Mycobacterium tuberculosis (Mtb) transmission. It is pulmonary TB in these older age groups that drives the global epidemic. There is a critical need for TB research and development of new, improved tools, especially new and more effective TB vaccines, in order to reach the World Health Organization?s (WHO) goal of ending the TB epidemic by 2035 and achieving the similar United Nations (UN) Sustainable Development Goal of ending TB by 2030. Live-attenuated vaccination strategies may be the best approach for conferring durable T-cell immune responses, believed to be necessary for protecting against TB. MTBVAC is a novel, live-attenuated Mtb vaccine based on deletion of two independent genes encoding major virulence factors, but retaining Mtb genes not present in BCG. Because MTBVAC is based on live, attenuated Mtb, and therefore presents a wider collection of Mtb- specific antigens to the host immune system than BCG, it may provide better protection. We aim, in a Phase 1b/2a, double-blind, randomized, BCG-controlled, dose-ranging study, to evaluate MTBVAC in adults with and without prior Mtb infection (Latent TB Infection; LTBI) to obtain critical safety and immunogenicity data to guide dose selection and to facilitate the advancement of MTBVAC into efficacy trials in TB endemic countries. Participants will have received previous BCG vaccination in infancy. The primary endpoint is comparison of the safety profile of intradermal MTBVAC injection at each of four dose levels compared to BCG revaccination. The proposed trial will be conducted in South Africa which has the second highest annual TB incidence in the world (834 per 100,000). Investment in MTBVAC is important as it has 1) shown promising results 2) is the only live attenuated Mtb vaccine currently in clinical development (first in class) and 3) contains additional antigens to M.bovis, the progenitor of the current vaccine BGC, and therefore may provide enhanced protection against TB.